4. Photodynamic Therapy of Malignant Tumors of Different Localizations
Evgeny Ph. Stranadko, Alexander A. Radaev
The “Magic Ray” Moscow Center of Laser Medicine, Moscow, Russia
Despite the latest advances in oncology, the problem of treating malignant diseases has not been resolved yet. In most cases, the treatment is beneficial at early stages of cancer. However, two thirds of patients reveal advanced cancer. Only a half of them undergo special treatment. However, surgery, radiotherapy, and combined treatment have limited capabilities for advanced cancer. The rates of recovery and five-year survival are below 10 % after such treatments. Most of the patients die of recurrences and metastases, which appear after radical treatment during the next two years. Until recently, there was no adequate technique for the treatment of such patients.
Besides that, many patients (up to 25 %) have operable cancer, but cannot undergo surgical treatment. This is because of serious associated diseases and age-related disorders. These patients often undergo organ-saving surgical treatment. However, such treatment also has a high rate of local recurrences. Until the last decade, there was no adequate treatment for these patients either.
The advent of photodynamic therapy (PDT) has considerably extended oncologic capabilities. Photodynamic therapy is a therapeutic technique for malignant diseases, and it is new in principle. This technique uses the photodynamic damaging of tumor cells by means of photochemical reactions.
Photodynamic therapy is a two-component therapeutic technique. The first component is a photosensitizer, which is accumulated in tumors. It remains in tumor cells longer than in healthy cells. The second component is optical radiation whose wavelength corresponds to the photosensitizer’s absorption peak. The local irradiation of a tumor containing the photosensitizer brings about photochemical reactions in it. These reactions generate singlet oxygen and free radicals that produce a toxic effect on tumor cells. As a result, the tumor is resorbed, and tumor cells are substituted by connective tissue.
Photodynamic therapy causes a local damage. On the one hand, this is due to the selective photosensitizer accumulation in tumor cells. On the other hand, the treatment is performed using a narrow and targeted laser radiation.
Photodynamic therapy offers a number of advantages over traditional techniques for treatment of malignant tumors (such as surgical operation, radiotherapy, and chemotherapy). First, PDT is highly selective and targeted in action. Second, it is free of surgical risks, serious damages, and systemic complications. Third, PDT sessions can be repeated as many times as needed. Fourth, a single PDT procedure enables both the treatment and fluorescent diagnostics. Finally, most patients exhibit a complete tumor resorption after a single PDT session, which can be performed under outpatient conditions.
Over the last several years, PDT was successfully applied with different photosensitizers. This technique was employed in the treatment of a variety of malignant tumors. Most of these tumors were cancers of the skin, lower lip, tongue, mouth, larynx, lung, bladder, gastrointestinal organs, and genitals (T.J. Dougherty, 1988; S. Marcus, 1992; H.I. Pass, 1993; O.K. Skobelkin with co-workers, 1992; and E.Ph. Stranadko with co-workers, 1992 to 1997).
Photodynamic therapy trends are as follows:
1. The first trend deals with early-stage cancer. The treatment is based on a radical program, aimed at the patient’s complete recovery. The program is used to treat skin cancer (such as multiple cancer, extended superficial cancer, as well as cancer with inconvenient localizations on the face and aural cavities). It is also employed to treat cancer of the lung, esophagus, bladder (such as superficial and multiple nodular cancer), and genitals.
2. The second trend is concerned with advanced cancer of the trachea, large bronchi, esophagus, and cardia. In this case, PDT is employed to recanalize hollow organs. As compared to laser photodestruction, PDT has fewer complications and longer tumor-free periods.
3. The third trend is based on the combined application of PDT and other techniques (such as polychemotherapy). This approach is employed to treat recurrent cancer of the skin, lower lip, and tongue. It is also used to treat intracutaneous metastases of melanoma and intracutaneous metastases and recurrences of breast cancer.
Currently, PDT is being tested for other applications. For example, PDT is applied in the surgical pretreatment for minimizing the volume of resection. It is also used in some non-radical treatments performed on tumors of cerebral and biliary-digestive regions. In these cases, PDT improves surgical and therapeutic efficiencies.
Photodynamic therapy can also produce considerable palliative and hemostatic effects. This is of special importance for treating extended decaying tumors. Photodynamic therapy is a harmless technique, and patients show good tolerance to it. As a result, PDT can be effectively combined with surgery, radiotherapy, and chemotherapy. Furthermore, short-term PDT treatment under outpatient conditions offers a great economic benefit.
The disadvantage of PDT is that the patient should remain heliophobic for a long time after photosensitizer injection. This requirement is associated to the photosensitivity of the patient’s skin. In order to avoid possible complications, the patient should exercise great caution. This is particularly important at the stage of acquiring clinical experience.
The aim of the current lecture is to outline PDT capabilities to the clinical practitioners of different branches (such as therapists, surgeons, and gynecologists). This lecture will also be of interest to oncologists and dermatologists in terms of PDT application.
Photodynamic Therapy Equipment
As a source of optical radiation, PDT widely employs argon pumped dye lasers and dye lasers pumped by a copper vapor laser (emitting at the wavelength of 630 nm). The last decade has seen an increasing number of PDT procedures performed with Photofrin photosensitizers and their analogs. These photosensitizers can work with gold vapor lasers (emitting at the wavelength of 627.8 nm). Gold vapor lasers are cheaper and smaller because they do not need water cooling.
As an example of argon pumped dye laser, consider the Innova 200 laser system (manufactured by “Coherent” U.S. Company).
1. Performance specification of argon pumped dye laser (Innova 200 laser system, USA):
- Radiation mode: continuous wave;
- Output radiation power: up to 5 W;
- Radiation wavelength: 630 nm;
- Readiness time: 5 min;
- Radiation power meter: available;
- Automatic exposure timer (1 to 9,999 sec): available;
- Guaranteed operation life: 1,000 h (the dye needs replacing every 1,000 hours of work);
- Power supply: 30 kW, three-phase current;
- Cooling agent: water;
- Cooling agent flow: 9.5 liter/min;
- Weight: 250 kg.
2. Performance specification of a tunable dye laser pumped by a copper vapor laser (Yakhroma-2 laser system, Russia):
- Radiation mode: pulsed (with frequency of 10 kHz);
- Output radiation power: up to 3 W;
- Radiation wavelength: 600 to 660 nm (depending on the dye);
- Readiness time: not less than 60 min;
- Radiation power meter: available;
- Automatic exposure timer (50 to 750 sec): available;
- Guaranteed operation life: 500 h (the dye needs replacing every 2 to 4 hours of work);
- Power supply: 5 kW, three-phase current;
- Cooling agent: water;
- Cooling agent flow: 2 to 4 liters/min;
- Weight: 400 kg.
Parameters that are of special importance for physicians operating laser systems are as follows: the output radiation power, readiness time (the shorter, the better), and guaranteed operation life. The last parameter shows the time during which the laser will produce radiation of a specified power. When this time expires, the output radiation power gradually decreases. This arises from the fading of the dye, which needs replacing. Hence, an essential disadvantage of lasers of this type is the need for replacing dyes or gas cylinders.
Diode lasers have a number of advantages over the above-described lasers. First, they are small and cost-effective. Second, diode lasers do not require water cooling. Third, they can operate off the 220 V supply line. Fourth, diode lasers have a longer operation life (without any replacement).
Laser radiation is delivered to a tumor through single quartz fibers. Such fibers are 1.5 to 3 meters in length and 400 to 600 micrometers in diameter.
In Russia, quartz fibers come in a wide range of modifications:
- with a microlens;
- with a sphere-shaped diffuser;
- with a cylinder-shaped diffuser (which can be 0.5, 1.0, 2.0, 3.0, and 4.0 cm long);
- with different side reflectors (which can be 0.5, 1.0, 2.0, and 4.0 cm long).
In the United States, quartz fibers are manufactured, for example, by “Photo Therapeutics, Inc.” These fibers come:
- with a sphere-shaped diffuser;
- with a cylinder-shaped diffuser (which can be 0.5, 1.0, 2.0, and 3.0 cm long).
Photodynamic therapy of internal organs is performed using commercially available endoscopes:
- laryngoscopes and bronchoscopes are employed to treat cancer of the larynx;
- bronchoscopes (such as the Friedel rigid bronchoscope and the “Karl Stortz” flexible bronchoscope) are used to treat cancer of the trachea and bronchi;
- fibrogastroscopes (such as the “Olympus” fibrogastroscope) are employed to treat cancer of the esophagus and stomach;
- rectoscopes find use in the treatment of cancer of the rectum;
- fibrocolonoscopes are used to treat cancer of the colon;
- the “Karl Stortz” cystoscopes are employed to treat cancer of the bladder.
When cancer affects internal organs, PDT should be performed using an endoscopic video system.
To deliver optical radiation to superficial tumors, one should use light-guiding fibers with a microlens at the end. Such light-guiding fibers produce a round pattern – a clear spot. The fiber is located at some distance from a tumor. It should be positioned such that the light spot would cover the tumor and part of surrounding tissue. The light spot should lap 2 to 3 cm over the tumor. Large tumors and tumors of irregular shapes should be irradiated using several optical fields.
Photodynamic therapy can also be performed using non-laser radiation sources, such as various light-emitting diodes (LEDs) and gas-discharge lamps with light-filters.
There is the following classification of photosensitizers:
à) Photosensitizers of the first generation
The evolvement of photodynamic therapy of cancer is closely connected with the development of the first photosensitizers based on porphyrins. Porphyrins play an important role in nature. They are part of such proteins as hemoglobin, myoglobin, catalase, peroxydase and a big group of cytochromes. These hemoproteins take part in transportation of oxygen and supply of energy to the body.
A big number of porphyrins were studied as sensitizers for PDT. The most promising among them was hematoporphyrin-IX, and on its basis R. Lipson and his colleagues got in 1961 the so-called “hematoporphyrin derivative” which T.J. Dougherty used to treat his first patients. Nowadays they still widely use medicaments on the basis of hematoporphyrin. This is Photofrin in the USA and Canada, Fotosan in Germany, HpD in China, Photohem in Russia. Numerous studies, including our researches, showed that the product produced by Lipson’s method consists of monomeric porphyrins, dimmers and high-molecular oligomers. The latter ones show most activity when used in PDT. Porphyrinic macrocycles in oligomers are joined by three types of linkages – ester (A), ether (B) and carbon-carbon linkages (C).
b) Photosensitizers of the second generation
Along with medicaments used now, new compounds are being researched which are known as sensitizers of the second generation. The main requirements to these medicaments can be put as follows: 1) they must have high selectivity to cancer cells and show low accumulation in normal cells; 2) possess low toxicity and easily eliminate from the body; 3) show low accumulation in skin; 4) be stable in storage and during introduction into the body; 5) possess good luminescence for reliable diagnostics of a tumor; 6) have high quantum yield of triplet state with energy not less than 94 kJ/mol; 7) have intensive absorption maximum in the range of 660 – 900 nm.
Chlorophyll-A and bacteriochlorophyll-A derivatives
The ranges of 660 – 740 nm and 770 – 820 nm have appropriate spectrum characteristics and high quantum yield of singlet oxygen.
Natural chlorophyll-A is not stable enough to be used in PDT. Higher stability is a quality of phaeophorbide-A which is produced by removal of magnesium ion and ester group (phytol). Phaeophorbide has intensive absorption peak in the range of 660 nm, and it generates singlet oxygen well. Its disadvantage is low solubility in water. That is why there have been suggested numerous phaeophorbide derivatives with two, three and more carboxyl groups.
Another important chlorophyll derivative is chlorin e6. Due to three acid residues, this sensitizer possesses high solubility in water. Among chlorin derivatives, the most effective ones are mono- and diamides with natural aspartic acid which are called ÌÀÑÅ and DÀÑÅ. They get better accumulated in a tumor and can be easily eliminated from the body.
Bacteriochlorophyll-A – the main photosynthetic pigment of purple bacteria – is different from chlorophyll-A in additional hydrogenation of the double bond between positions 7 and 8. This leads to a shift of the main absorption line to the near IR-spectra approximately by 100 nm. By analogy with chlorophyll-A, there were produced bacteriochlorophyll derivatives, and one of them which was made not so long ago, is bacteriopurpurine with the intensive absorption line in the 820 nm region. Bacteriochlorophyll derivatives, as far as their spectral and photophysical characteristics are concerned, are promising compounds for PDT, but researches in this field have been really carried out only over the last years.
Tookad is a natural palladium bacteriochlorophyll medicament. It was invented by Doctor Avigdor Scherz (Israel) in 1999. In a lab environment, Doctors A. Scherz and Y. Salomon showed that photoactivation of Tookad by fiber-optic radiation immediately after its introduction causes oxidative damage of tumor vessels, which results in tumor ischemia and its necrosis. Pharmacokinetic experiments were performed using cell cultures and laboratory animals. The effectivity of Tookad 90 days later after PDT in laboratory animals with subcutaneous tumors was 73 %, with bone tumors – 50 %.
Synthetic chlorins è bacteriochlorins
Along with natural chlorophylls, there is a big number of synthetic di- and tetrahydroporphyrins which have already undergone successfully biological and clinical trials.
In England, Professor R. Bonnett suggested tetra-hydroxyphenyl-chlorin (Foscan) and corresponding bacteriochlorin as a sensitizer. These compounds have intensive maximums in the range of 650 and 735 nm, they perfectly well generate singlet oxygen and have low phototoxicity. Chlorin under the trademark of Temoporphin has been successfully undergoing clinical trials.
Tetraazaporphyrins are porphyrins with four nitrogen atoms instead of meso-carbon groups. The compounds of this row which have been studied most of all, are phthalocyanines and naphthalocyanines.
Phthalocyanines (13, Ì = 2Í) have four benzene rings joined to a microcycle. One of their characteristics is a high-intensity peak in the range of 670 nm. There are a big number of phthalocyanines with different R substitutes and metallic ions in the microcycle. Complexes with zinc, aluminum and silicium show higher biological activity. Particularly good results have been gained for a zinc complex of phthalocyanine with four hydroxyl groups (13, Ì = Zn, R = OH) and cholesterin as axial ligand to central metallic ion.
Naphthalocyanines have absorption peak in the range of good light penetration through tissues at 750 – 780 nm, long living triplet condition and effectively generates singlet oxygen. One of the difficulties of using these compounds is their high hydropathy and, as a result, low solubility in water. One of the advantages of naphthalocyanines is the possibility to use them together with comparatively cheap and compact diode lasers. In conclusion, it should be noted that in 1994 clinical tests of the Russian medicament Photosense – aluminium sulphonated phthalocyanine were begun. This is the first use of phthalocyanines in PDT of cancer.
Photoditazine (a modified natural mix of chlorins from microalgae of Spirilina type, 90 % of which are chlorin e6) is a photosensitizer of the second generation aimed at photodynamic therapy. An absorption spectrum of the Photoditazine medicament has its maximum in the range of 662 ± 5 nm. The concentration of Photoditazine in blood serum reaches its maximum in 15 – 30 minutes and decreases fast, and one hour later after the introduction at a dose of 0.7 mg/kg it makes 10 mcg/l, and 24 hours later – 1 mcg/l. The concentration of the medicament in tumor tissues at an average is 15 – 20 times as high as that in surrounding healthy tissues, depending on the morphological structure of a tumor and makes 2 – 10 mcg/ml. More than 95 % of the medicament gets metabolized in the liver down to biladienes. The medicament is eliminated unchanged via stools (15 %) and urine (3 %). The main part of Photoditazine (98 %) is eliminated or metabolized within the first 28 hours.
Photodynamic Therapy Procedure
Photohem is a mixture of monomeric and oligomeric hematoporphyrin derivatives. Its maximum absorption is at the wavelength of 630 nm. This photosensitizer comes in sterile 50-ml glass vials. It represents a flavorless powder of dark-violet color. The Photohem sample weighs 260 mg, whereas the active ingredient weighs 200 mg. Photohem should be dissolved shortly before its intravenous injection. When a working solution is made, the vial is wrapped in lightproof paper. After that, 40 ml of a 0.9 % physiological solution of sodium chloride are added under sterile conditions. The vial is shaken and held for 3 to 5 min to let the foam settle down. A requisite Photohem dose is calculated from a 0.5 % concentration of the active ingredient (i. e., 1 ml of the prepared solution contains 5 mg of the compound) and the patient’s weight. The Photohem injection is calculated on the basis of 2.0 to 2.5 mg per 1 kg of the patient’s weight. The solution is injected intravenously (slowly) 24 – 48 hours before laser irradiation of a tumor. Photohem can also be applied interstitially. In this case, a 0.5 % Photohem solution is used. The solution amount depends on the tumor size.
Photoditazine is a 0.50 % concentrate for solution preparation for infusions. This photosensitizer comes in sterile 10-ml dark-brown glass vials. Each vial contains 50 mg (5 mg/ml) of active chlorin ingredient. A requisite Photoditazine dose is calculated from a 0.5 % concentration of the active ingredient and the patient’s weight. As a rule, this dose makes 0.7 – 1.4 mg/kg of body weight. A calculated dose of Photoditazine is dissolved in 100 ml of sodium chloride 0.9 % physiological solution. The Photoditazine solution is injected in a single-shot manner by means of intravenous drop-by-drop infusion within 30 minutes. 1 – 1.5 hours after the Photoditazine injection, a session of laser irradiation of a tumor is performed. Photoditazine can also be applied interstitially and its amount depends on the tumor size.
Energy Density, Power Density, and Exposure Time
The PDT exposure time depends on the effective energy density of optical radiation (Es). Energy density is measured in Joules per square centimeter (J/cm2). It is determined empirically and depends on the tumor’s type, histology, and localization.
Usually, the radiation energy density (Es) is in the range of 50 to 600 J/cm2. In the case of superficial tumors of the skin and mucous membrane, the radiation energy density (Es) is in the range of 50 to 150 J/cm2. In the case of advanced basal-cell carcinoma, exophytic squamous-cell carcinoma, metatypical skin cancer, and adenocarcinoma of internal organs with infiltration, the radiation energy density (Es) ranges between 200 and 300 J/cm2.
Another important PDT parameter is the radiation power density (Ps). It is measured in Watts per square centimeter (W/cm2). The radiation power density (Ps) is determined by dividing the output radiation power at the fiber’s end (P) into the area of laser exposure (S), namely the light spot area:
Ps = P / S.
Here, Ps is the radiation power density (W/cm2), P is the output radiation power at the fiber’s end (W), and S is the light spot area (cm2). The output radiation power at the light-guiding fiber’s end (P) is measured using a power meter.
The exposure time (T) is measured in seconds. It is determined by dividing the given radiation energy density (Es) in Joules/cm2, which should be administered to a tumor surface (namely the light dose), into the radiation power density (Ps) in W/cm2:
T = Es / Ps.
In order to simplify calculations, we give a table of radiation power density (Ps) as a function of both the output radiation power at the light-guiding fiber’s end (P) and the light spot diameter (D).
Indications to PDT for Malignant Tumors
General Indications to PDT
1. In the case of early primary cancer and early recurrences, PDT is indicated to patients with serious accompanying diseases and age-related disorders. It is performed according to a radical program when traditional techniques (such as surgery and radiotherapy) are contraindicated.
2. In the case of advanced tumors of tubular organs (such as the esophagus, the cardiac part of the stomach, the trachea, the rectum, as well as major, intermediate, and lobe bronchi), PDT is performed to recanalize these organs. It is employed as a palliative technique.
3. In the case of advanced decaying tumors complicated by intracutaneous metastases, PDT is combined with radiotherapy and chemotherapy. In this case, PDT is employed to stop bleeding and decrease the tumor volume.
Indications to PDT for Skin Cancer
1. Basal-cell carcinoma, squamous-cell carcinoma, and metatypical carcinoma (T1-3N0M0).
2. Recurrent and residual tumors resistant to traditional techniques.
3. Multiple tumors.
4. Extended tumors.
5. Inconvenient localizations in relation to surgical treatment (the periorbital area, nasal-and-labial fold, nose wings, aural cavity, and external ear-duct).
6. Patients’ refusal to the treatment with routine techniques.
Indications to PDT for Cancer of the Oropharyngeal Area
1. Squamous-cell carcinoma T1-3N0M0 characterized by the high risk of developing the complications after radiotherapy and surgery in elderly patients and patients with serious accompanying diseases.
2. Tumors resistant to routine treatments.
3. Recurrent and residual tumors.
4. Patients’ refusal to the treatment with routine techniques.
Indications to PDT for Lung Cancer
1. T1-2N0M0 central cancer localized in the trachea, major, intermediate, and lobe bronchi (exophytic and endophytic forms up to circular lesions, atelectasis are not a contraindication).
2. High risk of developing the complications after radiotherapy and surgery in elderly patients and somatically burdened patients with central lung cancer.
3. The lung cancer patients’ refusal to the treatment with routine techniques.
Indications to PDT for Esophageal Cancer
1. Primary T1N0M0 cancer with contraindications to surgical and/or combined treatment.
2. Early recurrences of cancer after radiotherapy.
3. Patients’ refusal to the treatment with routine techniques.
4. Palliative PDT aimed at recanalization in patients with obturating tumors.
Indications to PDT for Stomach Cancer
1. Primary T1N0M0 cancer of any histological structure, mucous and submucous membrane growth.
2. Early recurrences in anastomosis.
3. Palliative PDT in patients with stenosing cancer of the cardiac part of the stomach (with possible extension onto the esophagus) aimed at recanalization.
4. Patients’ refusal to the treatment with routine techniques.
Indications to PDT for Bladder Cancer
1. Superficial cancer of the bladder (primary or recurrent cancer).
2. T1N0M0 exophytic bladder cancer localized in the areas of the bottom, side walls (multiple lesions regardless of previous treatment are not a contraindication).
3. A recurrent character of the process, non-effectiveness of the treatment with routine techniques, and indications to cystectomy.
Indications to PDT for Breast Cancer
1. Ò1-2N0M0 Paget's cancer.
2. Recurrent breast cancer on the chest wall after surgical treatment.
3. Intracutaneous metastases after surgical, combined and complex treatment (the simultaneous administration of radiotherapy and chemotherapy is not a contraindication to PDT).
4. T1-2N0M0 primary (the nodular form) breast cancer when patients strongly refuse to be treated surgically and/or in patients with serious accompanying diseases.
Indications to PDT for Rectal Cancer
1. T1N0M0 rectal cancer in patients with contraindications to surgical treatment.
2. Palliative PDT aimed at recanalization in patients with obturating tumors.
Indications to PDT for Uterine Cervical Pathology
1. Pre-existing and precancerous uterine cervical diseases (ectopia, leukoplakia, endometriosis, stage I and II dysplasia, ectropion).
2. T1N0M0 uterine cervical cancer.
Contraindications to PDT
1. Cardiovascular and respiratory insufficiency.
2. Hepatic and renal diseases at the decompensation stage.
3. Systemic red lupus.
1. Allergic diseases.
2. Remote and regional metastases.
While considering the patient’s indications and contraindications to PDT, the physician has to employ the individual-base approach. The physician should also estimate the tumor process, possibilities of the risk of traditional treatment, severity of accompanying diseases, and possible complications.
Estimation of PDT Results
The tumor resorption period after PDT depends on a number of factors. The most important of them are as follows: the tumor size, infiltration depth, tumor localization, and radiation energy density. Normally, the tumor resorption period ranges from 2 days to 3 weeks.
When PDT is used to treat ulcerated and infiltrating tumors, it produces a pronounced damaging effect. It is characterized by extensive and deep hemorrhagic necrosis. In this case, the rejection of necrotic tissues and epithelization of the treated site may take from 2 to 10 weeks depending on the tumor size, necrotic depth, and PDT parameters. After the treatment, the most patients exhibit good cosmetic and functional results.
Estimation of PDT results is performed according to the following criteria:
1. A complete tumor resorption is verified by the absence of observable and palpable defects. This should also be confirmed by negative results of cytological and histological examinations.
2. A partial tumor resorption is verified when the maximum tumor size decreased not less than by 50 %, the tumor became invisible, but cytological and histological examinations show the tumor cells presence. A tumor recurrence after PDT is verified in the same manner.
3. Tumor reduction by less than 50 % or tumor status without changes is considered as no response.
In the case of skin cancer, PDT demonstrated a 100-% clinical effect. A complete tumor resorption was observed in 90 % of cases. The rest of the patients, who usually had extended skin tumors, showed a partial tumor resorption.
In the case of other tumor localizations, PDT efficiency was somewhat lower: between 70 and 90 %. A decrease in the PDT efficiency was connected with changes in the blood supply (for example, due to tumor recurrences after radiotherapy). It was also related to engineering difficulties in the administration of an adequate optical radiation dose to the entire tumor. In the case of early malignant tumors, PDT efficiency ranged between 90 and 100 % including a complete tumor resorption in 55 to 70 % of the patients.
Complications of PDT
An essential disadvantage of Photohem and some other photosensitizers that are used at present in Russia and abroad is their long delay in skin. When photosensitizers are present in skin even at small concentrations, they make it highly photosensitive and phototoxic.
As a result, when patients violate a heliophobic regimen, they burn the first degree of face and an opened parts of the body. The burns are usually followed by skin pigmentation. When patients are often exposed to bright light for a short periods of time, they can get pigmentation without a burn.
Photodynamic therapy may bring about violent photochemical reactions and significant necrobiotic changes. The decay products of these reactions can cause intoxication and hyperthermia. These phenomena often take place in the case of multiple and extended tumors, especially in the case of ulcerated extended tumors.
Within the next few days after a PTD session, almost all of the patients get an edema. It arises from photochemical reactions inside biological tissues owing to interstitial dispersion of light. The most pronounced edema develops after PDT for skin of the face. This edema does not require special treatment and disappears within 3 to 4 days after the PDT session.
In rare cases, PDT with Photohem may cause herpes, which often affects the patient’s lips. Herpetic lesions may develop within 3 days to 2 weeks.
Photodynamic therapy for esophageal cancer may cause esophagitis. When optical radiation is overdosed, PDT may cause remote development of circular scars.
The PDT for bronchogenic or lung cancer may cause purulent endobronchitis, which needs anti-inflammatory therapy. The PDT for exophytic obturating cancer of the major bronchus is followed by bronchial tree sanitation performed 2 to 3 days later. The bronchial tree sanitation is needed to remove the detritus.
When PDT is used to treat superficial cancer of the bladder, it may cause fibrosis of the bladder wall, followed by a decrease in the bladder volume. This effect takes place when the entire internal surface of the bladder is subjected to irradiation.
In some patients, PDT may cause remote development of parestesia and induration of subcutaneous cellular tissues in the exposed site.
In general, the rate of complications associated with PDT does not exceed 5 %.
Prevention of Complications
As was mentioned, Photohem penetrates the skin and remains in it for a long time. After the intravenous photosensitizer injection, the patient should observe a heliophobic regimen for 3 to 4 weeks. This means that he or she has to avoid bright sunlight, both the direct one and the diffused one. Under indoor conditions, the patient can be illuminated by light of not more than 50 lux.
To prevent complications connected with hyperphotosensitivity, the patient should employ sun-protection creams and the ointments. These agents should be applied soon after finishing the Photohem injection. Sun-protection agents should contain compounds filtering and detaining the sunlight. In particular, these agents should filter and detain radiation at the band of Photohem absorption peak, namely at the Soret band (400 nm). Such sun-protection ointments are produced by many cosmetic companies (for example, by the L’Oleral company).
Basic mechanisms of the photodynamic destruction of a tumor work on the 5th - 7th days after PDT session, then there is a realization of medical effect. At this moment it is recommended that the patient should take antioxidant compounds (such as beta-carotene, vitamins C and E).
The proper selection of optical radiation doses makes it possible to avoid complications connected with the photodynamic destruction of a tumor and surrounding healthy tissues. The maximum radiation power density is often limited by capabilities of laser radiation source, whereas the radiation energy density depends on the physician’s experience, tumor features, and tumor localization. The radiation energy density determines the rate of photodynamic destruction, the depth of necrotic lesions, and the depth of damage of surrounding and underlying tissues.
In order to decrease the rate and severity of complications, one needs to employ special methods for separation of both the total drug dose and the total light dose. The application of these methods makes it possible to improve the PDT efficiency.